Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[CH2:15][C:16]([OH:18])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH:29]1[CH:30]=[CH:31]C2N(O)N=[N:35][C:33]=2[CH:34]=1.CCN=C=NCCCN(C)C.Cl.Cl.[F:52][C:53]([F:69])([F:68])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[S:60]NC1CCNCC1>CN(C=O)C.O>[O:18]=[C:16]([N:35]1[CH2:31][CH2:30][CH:29]([S:60][C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=2[C:53]([F:52])([F:68])[F:69])[CH2:34][CH2:33]1)[CH2:15][C:14]([NH:13][C:10]1[CH:11]=[N:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][CH:9]=1)=[O:19]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)nc1
Reactant: FC(F)(F)c1ccccc1SNC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCC(Sc2ccccc2C(F)(F)F)CC1)Nc1ccc(-c2ccccc2)nc1
Reaction time: 8 h
Yield: 66.9 %

Procedure:
To a stirred solution of N-(6-phenyl-pyridin-3-yl)-malonamic acid (0.07 g, 0.00024 mole) in DMF (1 mL) was added DIPEA (0.153 g, 0.00120 mole), HOBt (0.039 g, 0.000286 mole) and EDCI.HCl (0.055 g, 0.00029 mole). After 2 minutes (2-trifluoromethyl-phenylsulfanyl)-piperidin-4-yl-amine hydrochloride (0.085 g, 0.00029 mole) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 80.2 mg (67%) of 3-oxo-N-(6-phenyl-pyridin-3-yl)-3-[4-(2-trifluoromethyl-phenylsulfanyl)-piperidin-1-yl]-propionamide. LC-MS purity: 501.15 (M+1)+, 95.38%, 1H NMR (DMSO-d6): δ 10.5 (s, 1H), 8.8 (d, 1H), 8.2 (d, 1H), 8.1 (d, 2H), 8.0 (d, 1H), 7.7 (d, 1H), 7.6-7.4 (m, 5H), 7.2 (t, 1H), 4.3 (d, 1H), 3.9 (d, 1H), 3.7-3.6 (m, 3H), 3.3-3.2 (m, 1H), 3.0 (m, 1H), 2.0 (m, 2H), 1.7-1.6 (m, 1H), 1.5-1.4 (m, 1H).
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]#[N:12].O=[C:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[C:19](OC)=[O:20].C([O-])(=O)C.[NH4+]>O>[OH:20][C:19]1[N:3]2[C:2](=[N:1][C:5]3[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=32)[C:10]([C:11]#[N:12])=[C:14]2[CH2:18][CH2:17][CH2:16][C:15]=12
Reactant: COC(=O)C1CCCC1=O
Reactant: N#CCc1nc2c([nH]1)CCCC2
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: N#Cc1c2c(c(O)n3c4c(nc13)CCCC4)CCC2
Temperature: 140 °C
Reaction time: 2 h
Yield: 19.2 %

Procedure:
A mixture of 4,5,6,7-tetrahydro-1H-benzimidazol-2-yl acetonitrile (8.5 g), methyl 2-oxocyclopentanecarboxylate (7.5 g) and ammonium acetate (20.3 g) was stirred at 140° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added, and extraction was performed with chloroform. The organic layer was washed with a saturated brine, dried over anhydrous sodium sulfate, and concentrated reduced pressure. The residue was solidified using hexane/EtOAc to obtain 11-hydroxy-2,3,6,7,8,9-hexahydro-1H-cyclopenta[4,5]pyrido[1,2-a]benzimidazole-4-carbonitrile (2.56 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH2:17][N:16]([C:21](OC(C)(C)C)=[O:22])[CH2:15]3)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.C(OCC)(=O)C.[CH2:35]([O:37][C:38]([C@@H:40]1[CH2:42][C@H:41]1C(O)=O)=[O:39])[CH3:36].CCN=C=NCCCN(C)C>ClCCl.CO.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH2:17][N:16]([C:21]([C@@H:41]2[CH2:42][C@H:40]2[C:38]([O:37][CH2:35][CH3:36])=[O:39])=[O:22])[CH2:15]3)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)[C@@H]1C[C@H]1C(=O)O
Reactant: CCc1[nH]c(C(=O)Nc2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1C(=O)N1Cc2ccc(NC(=O)c3nc(Cl)c(CC)[nH]3)cc2C1
Reaction time: 0.33 h
Yield: 64.7 %

Procedure:
tert-Butyl 5-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-1,3-dihydro-2H-isoindole-2-carboxylate (described in Example (92a), 0.17 g, 0.42 mmol) was dissolved in dichloromethane (3 mL) and methanol (1 mL). A 4 N hydrochloric acid/ethyl acetate solution (15 ml, 60 mmol) was added, followed by stirring for 20 minutes. The solvent was evaporated under reduced pressure. The resulting residue was dissolved in dichloromethane (5 mL) and DMA (5 mL). trans-2-(Ethoxycarbonyl)cyclopropanecarboxylic acid (described in Wessjohann, Ludger A.; Fulhorst, Michael; Zakharova, Svetlana, Pol. J. Chem., 80, 4, 2006, 673-678, 87 mg, 0.55 mmol), WSC (191 mg, 1 mmol) and DMAP (10 mg) were added, and the mixture was stirred at room temperature for one hour. The reaction solution was concentrated, diluted with ethyl acetate, washed with water and brine, and dried over anhydrous magnesium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: chloroform/methanol=95/5, 90/10) to obtain 117 mg of the title compound as a light brown solid (65%).
Reaction SMILES: C(N([CH2:17][C:18]([OH:20])=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.IC1C=CC([OH:28])=CC=1.OO.[N:31]1[C:36]2[CH:37]=[CH:38]C=[N:40][C:35]=2[CH:34]=[CH:33][N:32]=1>C(O)C(N)(CO)CO.CS(C)=O>[CH:37]1[CH:36]=[C:35]([NH2:40])[C:34]2[C:33]([NH:32][NH:31][C:18](=[O:20])[C:17]=2[CH:38]=1)=[O:28]
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Reactant: c1cnc2ccnnc2c1
Reactant: Oc1ccc(I)cc1
Agent: NC(CO)(CO)CO
Agent: OO
Solvent: CS(C)=O
Product: Nc1cccc2c(=O)[nH][nH]c(=O)c12
Reaction time: 0.02 h

Procedure:
The pyridopyridazine compound (L-012) as obtained in Example 3 and luminol were dissolved at the concentration of 0.2 mM in 0.2 M Tris buffer (pH 8.6) containing 0.1 mM EDTA. In test tubes were put 990 μl respectively of the solutions, and to each of the solutions was added 10 μl of a dimethylsulfoxide (DMSO) solution of 40 mM p-iodophenol as a chemiluminescent enhancer, followed by mixing. In other test tubes were put 50 μl of each of the mixtures, whereto 100 μl of a 0.2 M Tris buffer (pH 8.6) containing horseradish peroxidase at the concentrations of 10 pg/ml, 100 pg/ml 1 ng/ml or 10 ng/ml. By further adding 50 μl of Tris buffer (pH 8.6) containing of 0.6 mM H2O2 to each of the tubes, chemiluminescent reaction was initiated. The measurement was carried out for the luminous amounts for 10 seconds between 60 seconds later and 70 seconds later after addition of H2O2. The results are tabulated in Table 3. From Table 3, it was shown that the pyridopyridazine compound of Example 3 (L-012) provides about 4 to 20 times as great chemiluminescent amounts as luminol. The sodium salt of L-012 showed the same chemiluminescence activity as L-012.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:28]([N:30]([C:34]1([C:40]#[CH:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:31][CH2:32][OH:33])[CH3:29]>>[CH2:28]([N:30]([C:34]1([C:40]#[C:41][C:16]2[CH:15]=[CH:14][C:13]3[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:26])([F:27])[F:1])=[CH:8][CH:7]=4)=[N:10][S:11][C:12]=3[CH:17]=2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:31][CH2:32][OH:33])[CH3:29]
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1)C(F)(F)F
Reactant: C#CC1(N(CC)CCO)CCCCC1
Product: CCN(CCO)C1(C#Cc2ccc3c(-c4ccc(C(F)(F)F)cc4)nsc3c2)CCCCC1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester and 2-[Ethyl-(1-ethynyl-cyclohexyl)-amino]-ethanol were converted to yield 2-(Ethyl-{1-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-ylethynyl]-cyclohexyl}-amino)-ethanol as brown oil, MS: 473.3 (MH+).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]12[CH2:17][N:16]([C:18]3[C:27]([F:28])=[C:26]4[C:21]([C:22](=[O:35])[C:23]([C:32]([OH:34])=[O:33])=[CH:24][N:25]4[CH:29]4[CH2:31][CH2:30]4)=[C:20]([F:36])[C:19]=3[F:37])[CH2:15][CH:14]1[CH2:13][CH2:12][O:11]2)=O)(C)(C)C.[ClH:38]>>[ClH:38].[NH2:8][CH2:9][C:10]12[CH2:17][N:16]([C:18]3[C:27]([F:28])=[C:26]4[C:21]([C:22](=[O:35])[C:23]([C:32]([OH:34])=[O:33])=[CH:24][N:25]4[CH:29]4[CH2:31][CH2:30]4)=[C:20]([F:36])[C:19]=3[F:37])[CH2:15][CH:14]1[CH2:13][CH2:12][O:11]2
Reactant: CC(C)(C)OC(=O)NCC12CN(c3c(F)c(F)c4c(=O)c(C(=O)O)cn(C5CC5)c4c3F)CC1CCO2
Agent: Cl
Product: NCC12CN(c3c(F)c(F)c4c(=O)c(C(=O)O)cn(C5CC5)c4c3F)CC1CCO2

Procedure:
In an analogous manner to Example 1B, the product from step A is reacted with half-concentrated hydrochloric acid to give 7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]-oct-7-yl)-1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride with a melting point of 175°-177° C. (with decomposition).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]12)=[O:4].C(=O)(O)[O-].[Na+].O.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC(C)=O>[C:27]([NH:1][CH2:2][C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]12)=[O:4])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC1(C)S[C@@H]2C(NC(=O)CN)C(=O)N2C1c1nnn[nH]1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)S[C@@H]2C(NC(=O)CNC(=O)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Reaction time: 0.33 h
Yield: 37 %

Procedure:
To a stirred solution of 0.80 g. (2.7 mmole) of 6-(2-aminoacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam and 0.453 g. (5.4 mmole) of sodium bicarbonate in 21 ml. of water and 15 ml. of acetone at 0°-5° C. is added 0.32 ml. (2.8 mmole) of benzoyl chloride. Stirring is continued for a further 20 minutes at ca. 0° C., and then the acetone is removed in vacuo. The aqueous residue is extracted with ethyl acetate and the extracts are discarded. The pH of the aqueous phase is adjusted to 2.0, and the product is extracted into ethyl acetate. The solvent is dried (Na2SO4), and then concentrated in vacuo to give 150 mg. (37% yield) of the title compound, m.p. 85°-93° C. IR (KBr disc): 1785 cm-1 (β-lactam) and 1695 cm-1 (amide I). NMR (in D2O): 7.90 ppm (m,2 H), 7.50 ppm (m,3H), 5.82 ppm (s,1H), 5.58 ppm (s,1H), 5.19 ppm (s,1H), 4.25 ppm (m,2H), 1.67 ppm (s,3H), 1.67 ppm (s,1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([CH3:14])([CH3:13])[CH3:12].[Cl:15][CH2:16]OC.S(=O)(=O)(O)O>>[Br:1][C:2]1[C:3]([C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1)[CH2:16][Cl:15]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1Br
Reactant: COCCl
Agent: O=S(=O)(O)O
Product: CC(C)(C)c1c(Br)cc([N+](=O)[O-])cc1CCl
Temperature: 0 °C

Procedure:
A mixture of 30 parts of 2-bromo-1-tert-butyl-4-nitrobenzene and 30 parts of chloromethylmethyl ether is stirred vigorously while adding dropwise 20 parts of 60% fuming sulfuric acid. The resultant mixture is allowed to stand until the apparent reaction ceases and is then poured into ice water. The solid is removed by filtration and washed with water to give 3-bromo-2-tert-butyl-5-nitrobenzyl chloride.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18](NC1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[C:38]1([CH:44]([NH2:51])[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH:13][S:14]([CH2:17][C:18]([NH:51][CH:44]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:19])(=[O:16])=[O:15])([CH3:11])[CH3:12]
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Reactant: NC(c1ccccc1)c1ccccc1
Product: CC(C)c1cccc(C(C)C)c1NS(=O)(=O)CC(=O)NC(c1ccccc1)c1ccccc1

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with diphenylmethylamine, mp 166°-167° C.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH2:23]([O:30][C:31]([N:33]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]([CH2:40][OH:41])[CH2:34]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCOC(C)=O>C(Cl)Cl>[CH2:23]([O:30][C:31]([N:33]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]([CH:40]=[O:41])[CH2:34]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(OCc1ccccc1)N1CCCCC(CO)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=CC1CCCCN(C(=O)OCc2ccccc2)C1
Reaction time: 1 h
Yield: 23.5 %

Procedure:
Dess-Martin periodinane (2.78 g, 6.56 mmol) was slowly added to a stirring 0° C. solution of 3-hydroxymethyl-azepane-1-carboxylic acid benzyl ester (146) (1.2516 g, 5.02 mmol) in CH2Cl2 (18.2 mL). The reaction was stirred for 1 hour until the reaction was judged complete by HPLC. The reaction was concentrated in vacuo, and a minimal amount of CH2Cl2 was added. Et2O was added to precipitate the periodinane by-product, and the reaction was filtered, concentrated, and immediately purified through an automated silica get column with 1:1 Hexanes:EtOAc to obtain pure 3-formyl-azepane-1-carboxylic acid benzyl ester (147) (0.3086 g) in 62% yield.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Li+].[CH3:17]C([N-]C(C)C)C.IC>C1COCC1.C(OCC)C>[CH3:17][C:8]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CI
Product: CCOC(=O)C1(C)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 1 h
Yield: 129.5 %

Procedure:
Ethyl 1,4-dioxaspiro[4,5]decane-8-carboxilate (2) (5.8 g) was dissolved under a nitrogen atmosphere in dry THF (60 mL) and cooled in a dry ice/isopropanol bath to −78° C. LDA (2M solution in THF/n-heptane/ethylbenzene, 20 mL, 40 mmol) was added dropwise to the stirred solution and the mixture was allowed to warm to room temperature for 30 minutes. The reaction mixture was again cooled to −78° C. and to it was added a solution of iodomethane (5.5 g, 39 mmol) in dry THF (15 mL) using a syringe pump over 20 minutes. This mixture was stirred at −78° C. for 1 h. The reaction mixture was allowed to reach room temperature. The reaction mixture was then diluted with ethyl ether (100 mL) and the organic layer was washed with saturated aqueous ammonium chloride solution (2×50 mL) and brine (1×50 mL), then dried over magnesium chloride, filtered, and concentrated in vacuo to give a yellow-brown oil (8 g). The oil was purified by flash column chromatography [petroleum ether-ethyl ether (2:1)] to give 3 (5.22 g, 85%) as a colorless oil: 1H NMR (CDCl3) δ 4.14 (2H, q, J=7.1 Hz), 3.93 (4H, s), 2.13 (2H, m), 1.64 (6H, m), 1.25 (3H, t, J=7.1 Hz), 1.18 (3H, s); 13C NMR (CDCl3) δ 177.2, 108.7, 64.4, 60.6, 42.5, 33.1, 32.3, 26.2, 14.4.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8][C:9](=[O:17])[C:10]3[CH:16]=[CH:15][CH:14]=[N:13][C:11]=3[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.CN(C=O)C.[H-].[Na+].[H][H].[CH2:27](I)[CH3:28]>>[CH2:27]([N:8]1[C:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=2[NH:12][C:11]2[N:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]1=[O:17])[CH3:28]
Reactant: [H][H]
Reactant: CCI
Reactant: Cc1cccc2c1NC(=O)c1cccnc1N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)c2cccnc2Nc2cccc(C)c21
Temperature: 60 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
To a stirred suspension of 1.1 g (5 mmol) 6,11-dihydro-7-methyl-5H-pyrido-[2,3-b][1,5]benzodiazepin-5-one in 20 ml of dry DMF 0.13 g (5.5 mmol) of sodium hydride was added portionwise at room temperature. Once the evolution of hydrogen had ceased, the mixture was heated to 60° C. for 2 h, cooled to 10° C., and then 0.86 g (5.5 mmol) of ethyl iodide was added. The reaction mixture was stirred at room temperature overnight and then concentrated. The residue was poured into water, the solid collected, washed, dried and column chromatographed on 60 g of dry silica gel. The product (second fraction) was eluted with methylene chloride and methylene chloride/methanol 99/1 to give 0.6 g (80% of theory) of 6,11-Dihydro-6-ethyl-7-methyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one m.p. 186°-188° C.
Reaction SMILES: C(OC(=O)[C:5]([C:31]#[N:32])([N:13]=[N:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.C(O)(=O)C.Cl.C(=O)(O)[O-].[Na+]>O>[F:23][C:22]([F:24])([F:25])[C:21]([C:18]1[CH:17]=[CH:16][C:15]([NH:14][N:13]=[C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:31]#[N:32])=[CH:20][CH:19]=1)([OH:30])[C:26]([F:27])([F:29])[F:28]
Reactant: CCOC(=O)C(C#N)(Cc1ccccc1)N=Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#CC(Cc1ccccc1)=NNc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1

Procedure:
A solution of 238 mg. (0.5 mmol) of α-cyano-α-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenylazo]benzenepropanoic acid ethyl ester in 3 ml. of acetic acid and 1 ml. of concentrated hydrochloric acid was stirred at room temperature for 30 minutes, diluted with water, made basic with sodium bicarbonate and extracted with ether. The ether extracts were dried and concentrated. The residue was dissolved in 1:1 benzene-dichloromethane and passed over a little silica gel. The eluate was concentrated and crystallized from hexane to give α-[1-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]hydrazin-2-ylidene]benzenepropanenitrile Isomer A as yellow crystals, m.p. 90°-92°.
Reaction SMILES: [CH2:1]([NH:10][C:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:17][CH:18]=2)[NH:13][C:12]=1[C:24]([O:26]CC)=[O:25])[C:2](C1C=CC=CC=1)=O.C(OC(OC(C)(C)C)=O)(O[C:32](C)([CH3:34])[CH3:33])=O.[O:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1.CN(C1C=CC=CN=1)C>C(OCC)(=O)C>[CH2:2]([CH2:1][NH:10][C:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([F:21])([F:22])[F:23])=[CH:17][CH:18]=2)[NH:13][C:12]=1[C:24]([OH:26])=[O:25])[C:48]([C:47]1[CH:34]=[CH:32][CH:33]=[CH:45][CH:46]=1)=[O:44]
Reactant: CCOC(=O)c1[nH]c2cc(C(F)(F)F)ccc2c1NCC(=O)c1ccccc1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Product: O=C(CCNc1c(C(=O)O)[nH]c2cc(C(F)(F)F)ccc12)c1ccccc1
Reaction time: 8 h
Yield: 66 %

Procedure:
Mix 3-[(phenacyl)amino]-2-carbethoxy-6-trifluoromethylindole (390 mg, 1.04 mmol), di-tert-butyl dicarbonate (249 mg, 1.14 mmol), tetrahydrofuran (10 mL), dimethylaminopyridine (33 mg, 0.32 mmol) and stir overnight. Dilute the reaction with ethyl acetate, wash with 1M HCl, water, dry over magnesium sulfate, filter and concentrate in vacuo. Purify by flash chromatography (15% ethyl acetate/hexane) to yield the title compound as an amber oil (320 mg, 66%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[NH:12]1[C:20]2[C:15](=[CH:16][C:17]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=4)[CH2:24][CH2:23]3)=[CH:18][CH:19]=2)[CH:14]=[CH:13]1>>[CH3:37][CH:36]([CH3:38])[C:35]([NH:34][C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([CH:25]2[CH2:24][CH2:23][N:22]([CH2:21][C:17]3[CH:16]=[C:15]4[C:20](=[CH:19][CH:18]=3)[N:12]([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=3)[CH:13]=[CH:14]4)[CH2:27][CH2:26]2)[CH:29]=1)=[O:39]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Reactant: FC(F)(F)c1cccc(I)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4c(ccn4-c4cccc(C(F)(F)F)c4)c3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-3-(trifluoromethyl)benzene and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: 1H NMR (400 MHz, CDCl3) δ 7.80-6.94 (m, 12H), 6.69 (d, 1H, J=3.6 Hz), 3.36 (s, 2H), 3.10-3.00 (m, 2H), 2.58-2.42 (m, 2H), 2.16-2.02 (m, 2H), 1.85-1.75 (m, 4H), 1.25 (d, 6H, J=7.2 Hz); ESMS m/e: 520.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:31])[N:14]([CH3:30])[N:15]=[C:16]([CH2:28][OH:29])[C:17]=1S(C1C=CC(C)=CC=1)(=O)=O)[CH3:2].[OH-:32].[Na+].Cl>CN1CCN(C)C1=O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:31])[N:14]([CH3:30])[N:15]=[C:16]([CH2:28][OH:29])[C:17]=1[OH:32])[CH3:2]
Reactant: [OH-]
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(=O)(=O)c2ccc(C)cc2)c(CO)nn(C)c1=O
Agent: Cl
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Product: CCc1cc(C)cc(CC)c1-c1c(O)c(CO)nn(C)c1=O
Temperature: 70 °C
Reaction time: 12 h
Yield: 47 %

Procedure:
To a solution of 4-(2,6-diethyl-4-methylphenyl)-6-hydroxymethyl-5-(4-methylphenylsulfonyl)-2-methyl-3(2H)-pyridazinone (2.58 g, 5.85 mmol) in 1,3-dimethylimidazolidinone (30 ml) was added 2N aqueous sodium hydroxide solution (15 ml), and stirred at 70° C. for 12 hours. After cooling to room temperature, 2N hydrochloric acid (25 ml) was added, and extracted with ethyl acetate 2 times. The combined organic layer was washed with water 2 times, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1 to 1:2) to give 842 mg of Compound (I-24-1) (yield: 47%) as solid.
Reaction SMILES: [H][H].O.O[N:5]1[C:9]2C=[CH:11][CH:12]=[CH:13][C:8]=2N=N1.C(N=C=NC(C)C)(C)C.C(N(C(C)C)C(C)C)C.[Cl:32][CH2:33][Cl:34]>>[Cl:32][CH2:33][Cl:34].[NH:5]1[CH2:11][CH2:12][CH2:13][CH2:8][CH2:9]1
Reactant: [H][H]
Reactant: On1nnc2ccccc21
Agent: CC(C)N=C=NC(C)C
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C1CCNCC1
Reaction time: 0.5 h

Procedure:
If R1 and R2 are both hydrogen preferably the first stage is carried out as follows: the aminooxy-2-chlortrityl polystyrene resin is mixed in a suitable solvent, such like dichloromethane, with a compound of formula VI, in which R1 and R2 are both hydrogen, in the presence of 1-hydroxybenzotriazole hydrate and 1,3-diisopropylcarbodiimide and the resulting mixture then treated with N-ethyl-diisopropylamine at room temperature. The obtained resin is isolated and shaken twice for a period of 15 to 45 minutes, e.g. 20 minutes, with a freshly prepared dichloromethane/piperidine solution to provide a compound of formula VII, in which the black circular plane indicates that the compound is bound to a polymer resin and in which R1 and R2 are both hydrogen.